Pharmaceutical Research

, Volume 25, Issue 1, pp 48–54 | Cite as

Mechanistic Understanding of Oral Drug Absorption Enhancement of Cromolyn Sodium by an Amino Acid Derivative

  • Adam W. G. Alani
  • Joseph R. Robinson
Research Paper



Examine the oral absorption enhancement mechanism of cromolyn sodium by sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) by evaluating the effect of SNAC on cromolyn sodium lipophilicity and changes in Caco-2 cell membrane fluidity.

Materials and Methods

Standard Shake-flask method was used to evaluate the effect of SNAC on the lipophilicity of cromolyn sodium. The measurements were carried out in three partitioning solvents with varying hydrogen-bonding properties. Steady state fluorescence emission anisotropy technique was used to evaluate the effect of SNAC with/without cromolyn sodium on Caco-2 cell membrane fluidity.


The lipophilicity measurements showed that SNAC had no influence on the lipophilicity of cromolyn sodium in the three partitioning solvent systems. The findings of the steady-state fluorescence anisotropy showed that SNAC increases the membrane fluidity of the Caco-2 cells in a concentration dependent manner. The increase in fluidity with SNAC was seen in the presence and absence of cromolyn sodium and the presence of cromolyn sodium did not augment the effect of SNAC on membrane fluidity.


The increase in membrane fluidity by SNAC plays a pivotal role in the permeation enhancement mechanism of cromolyn sodium. Therefore, the increase in permeation is a result of changing Caco-2 cell membrane fluidity resulting in change in membrane integrity and not due to an increase in the lipophilicity of cromolyn sodium through its interaction with SNAC.

Key words

Caco-2 cell line cromolyn sodium GI tract drug absorption lipophilicity membrane fluidity SNAC 



The authors would like to thank the School of Pharmacy, University of Wisconsin-Madison for financial support.


  1. 1.
    S. Budavari, M. J. O’Neil, A. Smith, and P. E. Heckelman. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals (Merck Index), MERCK & CO., Inc., Rahway, NJ, 1989.Google Scholar
  2. 2.
    H. S. White. Histamine and antihistamine drugs. In Remington (ed.), The Science and Practice of Pharmacy, Williams & Wilkins, Philadelphia, 2000, pp. 1464–1476.Google Scholar
  3. 3.
    T. Mori, K. Nishimura, S. Tamaki, S. Nakamura, H. Tsuda, and N. Kakeya. Pro-drug for the oral delivery of disodium cromoglycate. Chem. Pharm. Bull. 36:338–344 (1988).PubMedGoogle Scholar
  4. 4.
    PDR®. Physician’s Desk Reference, Thomson PDR, 1992.Google Scholar
  5. 5.
    A. Yoshimi, H. Hashizume, S. Tamaki, H. Tsuda, F. Fukata, K. Nishimura, and N. Yata. Importance of hydrolysis amino acid moiety in water-soluble prodrug of disodium cromoglycate for increased oral bioavailibility. J. Pharmacobio-Dyn. 15:339–345 (1992).PubMedGoogle Scholar
  6. 6.
    A. Leone-Bay, H. Leipold, D. Sarubbi, B. Variano, T. Rivera, and R. A. Baughman. Oral delivery of sodium cromolyn: preliminary studies in vivo and in vitro. Pharm. Res. 13:222–226 (1996).PubMedCrossRefGoogle Scholar
  7. 7.
    Emisphere Technology. Emisphere’s oral cromolyn sodium program,
  8. 8.
    M. Goldbege. Oral macromolecule delivery: review of the large and expanding clinical database. Winter symposium & 11th International symposium on recent advanced drug delivery systems, Salt Lake city, Utah, 2003.Google Scholar
  9. 9.
    S.-J. Wu. Mechanistic studies on the Enhanced Mucosal Transport of Human Growth Hormone by Certain Amino Acid Derivatives, School of Pharmacy, University of Wisconsin, Madison, 1999.Google Scholar
  10. 10.
    B. N. Singh and S. Majuru. Oral delivery of therapeutic macromolecules: a prospective using the eligenTM technology. Drug Deliv. Technol. 3:53–62 (2003).Google Scholar
  11. 11.
    D. Brayden, E. Creed, A. O’Connell, H. Leiopold, R. Agarwal, and A. Leone-Bay. Heparin absorption across the intestine: Effect of Sodium N-[8-(2-Hydroxybenzoyl)amino]Caprylate in rat In situ Instillations and in Caco-2 monolayers. Pharm. Res. 14:1772–1778 (1997).PubMedCrossRefGoogle Scholar
  12. 12.
    B. Li. Non-covalent Carrier Enhanced Protein Absorption-cellular and Subcellular Mechanistic Studies, School of Pharmacy, University of Wisconsin, Madison, 2001.Google Scholar
  13. 13.
    S.-J. Wu and J. R. Robinson. Transcellular and lipophilic complex-enhanced intestinal absorption of human growth hormone. Pharm. Res. V16:1266–1272 (1999).CrossRefGoogle Scholar
  14. 14.
    X. Ding, P. Rath, R. Angelo, T. Stringfellow, E. Flanders, S. Dinh, I. Gomez-Orellana, and J. R. Robinson. Oral absorption enhancement of cromolyn sodium through noncovalent complexation. Pharm. Res. 21:2196–2206 (2004).PubMedCrossRefGoogle Scholar
  15. 15.
    J. C. Dearden and G. M. Bresnen. The measurement of partition coefficients. Quant. Struct.-Act. Relatsh. 7:133–144 (1988).CrossRefGoogle Scholar
  16. 16.
    B. D. Rege, J. P. Y. Kao, and J. E. Polli. Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. Eur. J. Pharm. Sci. 16:237–246 (2002).PubMedCrossRefGoogle Scholar
  17. 17.
    F. Giraud, M. Claret, K. R. Bruckdorfer, and B. Chailley. The effects of membrane lipid order and cholesterol on the internal and external cationic sites of the Na+–K+ pump in erythrocytes. Biochim. Biophys. Acta Biomembr. 647:249–258 (1981).CrossRefGoogle Scholar
  18. 18.
    X. Ding. Oral Absorption Enhancement of Cromolyn Sodium Through Non-covalent Complexation, Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, 2004, pp. 153.Google Scholar
  19. 19.
    A. Leone-Bay, D. R. Paton, J. Freeman, C. Lercara, D. O’Toole, D. Gschneidner, E. Wang, E. Harris, C. Rosado, T. Rivera, A. DeVincent, M. Tai, F. Mercogliano, R. Agarwal, H. Leiopold, and R. A. Baughman. Synthetic and evaluation of compounds that facilitate the gastrointestinal absorption of heparin. J. Med. Chem. 41:1163–1171 (1998).PubMedCrossRefGoogle Scholar
  20. 20.
    A. Leone-Bay, C. McInnes, N. Wang, F. DeMorin, D. Achan, C. Lercara, D. Sarubbi, S. Hass, J. Press, E. Barantseich, B. O’Broin, S. Milstein, and D. Paton. Microsphere formation in a series of derivatized a-amino acids: Properties, molecular modeling, and oral delivery of Salmon Calcitonin. J. Med. Chem. 38:4257–4262 (1995).PubMedCrossRefGoogle Scholar
  21. 21.
    A. Leone-Bay, N. Santiago, D. Achan, K. Chaudhary, F. DeMorin, L. Falzarano, S. Hass, S. Kalbag, D. Kaplan, H. Leiopold, C. Lercara, D. O’Toole, T.Rivera, C. Rosado, S. D, E. Vauocolo, N. Wang, S. Milstein, and R. A. Baughman. N-acelated-a-amino acids as novel oral delivery agents for proteins. J. Med. Chem. 38:4263–4269 (1995).PubMedCrossRefGoogle Scholar
  22. 22.
    J. L. Madara. Regulation of the movement of solutes across tight junctions. Annu. Rev. Physiol. 60:143–159 (1998).PubMedCrossRefGoogle Scholar
  23. 23.
    A. L. Daugherty and R. J. Mrsny. Transcellular uptake mechanisms of the intestinal epithelial barrier part one. Pharm. Sci. Technol. Today 2:144–151 (1999).CrossRefGoogle Scholar
  24. 24.
    E. C. Swenson and W. J. Curatolo. Intestinal permeability enhancement for proteins, peptides and other polar drugs: Mechanisms and potential toxicity. Adv. Drug Deliv. Rev. 8:39–92 (1992).CrossRefGoogle Scholar
  25. 25.
    E. S. Swenson, W. B. Milisen, and W. Curatolo. Intestinal permeability enhancement: efficacy, acute local toxicity, and reversibility. Pharm. Res. 11:1132–1142 (1994).PubMedCrossRefGoogle Scholar
  26. 26.
    W. L. Hayton, D. E. Gutman, and G. Levy. Effect of complex formation on drug absorption XI: Complexation of prednisone and prednisolone with dialkylpropionamide and its effect on prednisone transfer through artificial lipoid barrier. J. Pharm. Sci. 61:356–361 (1972).PubMedCrossRefGoogle Scholar
  27. 27.
    W. L. Hayton and G. Levy. Effect of complex formation on drug absorption XII: Enhancement of intestinal absorption of prednisone and prednisolone by dialkylpropionamide in rats. J. Pharm. Sci. 61:362–366 (1972).PubMedCrossRefGoogle Scholar
  28. 28.
    W. L. Hayton and G. Levy. Effect of complex formation on drug absorption XV: Structural requirement for enhancement of intestinal absorption of steroids by N,N-Di-n-propylpropionamide. J. Pharm. Sci. 61:649–651 (1972).PubMedCrossRefGoogle Scholar
  29. 29.
    W. L. Hayton and G. Levy. Effect of complex formation on drug absorption XIII: Effect of constant concentration of N,N-Di-n-propylpropionamide on prednisolone absorption from rate small intestine. J. Pharm. Sci. 61:367–371 (1972).PubMedCrossRefGoogle Scholar
  30. 30.
    W. L. Hayton, G. Levy, and C. Regardh. Effect of complex formation on drug absorption XIV: effect of N,N-Di-n-propylpropionamide on intestinal absorption of certain nonsteroid drugs in the rat. J. Pharm. Sci. 61:473–474 (1972).PubMedCrossRefGoogle Scholar
  31. 31.
    A. G. Alani and J. R. Robinson. Mechanistic understanding of oral drug absorption enhancement of cromolyn sodium by an amino acid derivative, Thirteenth International Symposium on Recent Advances in Drug Delivery Systems "Overcoming long-standing barriers", Salt Lake City, UT, 2007.Google Scholar
  32. 32.
    A. G. Alani and J. R. Robinson. Mechanistic Understanding of Oral Drug Absorption Enhancement of Cromolyn Sodium by an Amino Acid Derivative, School of Pharmacy, University of Wisconsin, Madison, 2007, p. 178.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.School of PharmacyUniversity of Wisconsin-MadisonMadisonUSA

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